As part of a program to evaluate long term genetic effects of opiate abuse and investigate amelioration with replacements or antagonists, a series of stress systems has been developed to test the capacity of the cell to handle potential mutagenic crises. Heroin addicts have an increased frequency of chromosome damage in unstressed leukocyte cultures and with the stress systems it can be shown that there is also a defect in their ability to repair far UV damage as measured by unscheduled DNA synthesis and an alteration in sister chromatid exchange response when stressed by UV and mitomycin C. The changes in UV induced DNA repair and chromosome aberrations were corrected after long term methadone maintenance. To further understand the implication of these findings studies are planned to evaluate repair of UV damage with a second assay system and also to use a chemical stress agent in place of UV. The rate at which methadone reverses both the biochemical and cytogenetic effects as measured with chemical and UV stresses will be determined and compared with the rates found for LAAM and naltrexone. These studies should be useful in determining the relative effectiveness of these treatment modalities at the genetic level. In conjunction with the in vivo experiments studies will also be initiated to attempt to reproduce these findings in vitro with fibroblast cultures to investigate the mechanism which produce these effects.